The cellular and molecular pathways involved in the effects of pro-inflammatory and immunoregulatory cytokines and chemokines on regulating HIV replication, as well as the effect of HIV on the ability of CD4+ T cells to respond to certain cytokines were investigated. Levels of in vitro HIV replication in CD4+ peripheral blood mononuclear cells (PBMCs) from HIV-infected subjects was found to reflect the net regulatory effects of endogenous HIV-suppressing beta chemokines (MIP-1alpha, MIP-1beta, RANTES) and endogenous HIV-inducing pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta). In addition, it was found that different in vitro stimulatory or cytokine conditions result in the selective replication of either macrophage or T cell-tropic endogenous viral strains in CD4+ PBMCs obtained from certain HIV-infected individuals. Analyses of the ability of various PBMC subsets to produce beta chemokines revealed that natural killer (NK) cells are able to produce high levels of beta-chemokines, particularly in response to IL-2 and IL-15, and that NK-derived beta-chemokines strongly inhibit macrophage-tropic HIV entry and replication in vitro. A metalloproteinase inhibitor known to block the secretion of TNF-alpha was found to dramatically suppress HIV replication in chronically HIV-infected cell lines, in vitro acutely HIV-infected PBMC and in PBMC from HIV-infected subjects; no detrimental effect on cellular activation or proliferation was observed. These findings have led to the initiation of a clinical trial in the U.K.. These studies demonstrate the complex interactions between cytokines, chemokines and HIV replication. In addition, we have demonstrated that several novel agents which interfere with cellular processes or factors important for the efficient replication of HIV can effectively inhibit HIV.